Preliminary evidence suggests that local plaque characteristics hold information about risk of atherosclerotic disease progression in both local and distant vascular territories. However, no prior prospective studies have established whether presence of lipid-rich necrotic core in the superficial femoral artery (SFA) predicts atherosclerotic disease progression either locally or in distant vascular beds. Among 360 participants with lower extremity peripheral arterial disease (PAD), this prospective study will determine for the first time whether the presence of magnetic resonance imaging (MRI)-measured lipid-rich necrotic core in SFA atherosclerotic plaque at baseline is associated with a) higher rates of acute coronary events and b) more rapid progression of lower extremity atherosclerosis at four-year follow-up, compared to the absence of lipid- rich necrotic core at baseline. Based on our preliminary data and that of others, we also hypothesize that circulating measures of oxidative stress (myeloperoxidase and nitrotyrosine) may communicate between vascular territories, linking atherosclerotic plaque vulnerability and risk of atherosclerotic disease progression between distinct vascular beds. Therefore, in our secondary study aims, we will determine whether higher baseline levels of myeloperoxidase and nitrotyrosine are associated with a) greater quantities of lipid-rich necrotic core in the SFA at baseline;b) higher rates of acute coronary events at four-year follow-up;and c) greater progression of lower extremity atherosclerosis at four-year follow-up. In exploratory analyses, we will determine whether associations of lipid-rich necrotic core in the SFA with acute coronary events and progression of lower extremity atherosclerosis are attenuated after additional adjustment for baseline levels of myeloperoxidase and nitrotyrosine. Our aims will be studied in 360 PAD participants in our NHLBI-funded Walking and Leg Circulation Study (WALCS) III cohort. Our well-characterized WALCS III cohort provides a unique opportunity to study the proposed aims for a relatively small marginal cost. Many patients suffer cardiovascular events despite optimal medical therapy. This proposed study is expected to provide new information about the pathophysiology of systemic atherosclerotic disease progression. If our hypotheses are correct, future studies should determine whether novel therapies that target molecular mediators of atherosclerotic disease progression, such as lipid-rich necrotic core or oxidative stress measures, can prevent progression of lower extremity and coronary atherosclerosis. PUBLIC HEALTH RELEVANCE: Lower extremity peripheral arterial disease (PAD) affects eight million men and women in the United States. This prospective study will determine whether among men and women with PAD, the presence of lipid-rich necrotic core in the superficial femoral artery is associated with a higher rate of progression of atherosclerosis in both local and distant vascular beds, compared to the absence of lipid-rich necrotic core in the superficial femoral artery. This study is expected to improve our understanding of the pathophysiology of systemic progression of atherosclerotic disease. This study is particularly important given that men and women in the United States are surviving longer with chronic diseases, such as atherosclerosis.